The sodium-dependent (“active”) glucose cotransporters (SGLTs), including SGLT 1 (found predominantly in the intestinal brush border) and SGLT2 (localized in the renal proximal tubule), have been significantly evaluated. In particular, SGLT2 has been found to be responsible for the majority of glucose reuptake by the kidneys. Inhibition of renal SGLT is now considered a useful approach to treating hyperglycemia by increasing the amount of glucose excreted in the urine (Arakawa K, et al., Br J Pharmacol 132:578-86, 2001; Oku A, et al., Diabetes 48:1794-1800, 1999). The potential of this therapeutic approach is further supported by recent findings that mutations in the SGLT2 gene occur in cases of familial renal glucosuria, an apparently benign syndrome characterized by urinary glucose excretion in the presence of normal serum glucose levels and the absence of general renal dysfunction or other disease (Santer R, et al., J Am Soc Nephrol 14:2873-82, 2003). Therefore, compounds which inhibit SGLT, particularly SGLT2, are promising candidates for use as antidiabetic drugs (reviewed in Washburn W N, Expert Opin Ther Patents 19:1485-99, 2009). In addition, since cancer cells show increased glucose uptake in comparison to their normal counterparts, SGLT inhibition has been proposed as a method for treating cancer by starving cancer cells. For example, studies suggest that SGLT2 plays a role in glucose uptake in metastatic lesions of lung cancer (Ishikawa N, et al., Jpn J Cancer Res 92:874-9, 2001). Thus, SGLT2 inhibitors may also be useful as anticancer agents.
In addition to pharmaceutical activity, a further consideration for the successful development of a medicament is the parameters which are connected with the physical nature of the active substance itself. Some of these parameters are stability of the active substance under various environmental conditions, stability of the active substance during production of the pharmaceutical formulation and the stability of the active substance in the final medicament compositions. In order to provide the necessary stability, the pharmaceutically active substance used in the medicament should be as pure as possible, leading to its stability in long-term storage under various environmental conditions.
Another factor to be considered is the uniform distribution of the active substance in the formulation, particularly when the active substance is to be given in low doses. To ensure uniform distribution, the particle size of the active substance can be reduced to a suitable level, e.g. by grinding. However, breakdown of the pharmaceutically active substance as a side effect of the grinding (or micronising) must be avoided. As a result, in view of the hard conditions required during the process, the active substance must be stable throughout the grinding process. Still further, if the active substance is not stable during the grinding process, a homogeneous pharmaceutical formulation with the specified amount of active substance is unlikely to be achieved in a reproducible manner.
Still another consideration associated with the grinding process for preparing the desired pharmaceutical formulation is the input of energy caused by this process and the stress on the surface of the crystals. This may in certain circumstances lead to polymorphous changes, to amorphization or to a change in the crystal lattice. Since the pharmaceutical quality of a pharmaceutical formulation requires that the active substance should always have the same crystalline morphology, the stability and properties of the crystalline active substance are subject to stringent requirements from this point of view as well.
Another consideration for the pharmaceutically active substance is stability in a formulation, which in turn gives rise to a longer shelf life of the particular medicament. In this instance, the shelf life is the length of time during which the medicament can be administered without any risk that the active substance has degraded. High stability of a medicament in the abovementioned pharmaceutical compositions under various storage conditions is therefore an additional advantage for both the patient and the manufacturer.
Furthermore, the availability of a well-defined crystalline form allows the purification of the drug substance by recrystallization.
Apart from the requirements indicated above, it should be generally borne in mind that any change to the solid state of a pharmaceutical composition which is capable of improving its physical and chemical stability gives a significant advantage over less stable forms of the same medicament.
The compound of the present invention has been prepared according to the methods of U.S. Publication No. 2009/0118201, filed Aug. 22, 2008, U.S. application Ser. No. 12/545,400, and PCT/US2009/054585, now WO2010/022313, both filed Aug. 21, 2009. The aim of the present invention is to provide a stable crystalline form of the compound which meets important requirements imposed on pharmaceutically active substances as mentioned above.